T699P
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialThreonine → Proline at position 699 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.914, DynaMut2 ΔΔG -0.14 kcal/mol (mild destabilising). Proline-introduction adjacent to W700 (Cat 2 outlier region).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | F825 | F825 | Preserved |
| Polar contact | F825 | — | Lost |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Likely pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- This rests on a single submitter (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) · under-sampled | 0.000090% | 1 / 1,111,814 | 0 | — |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
Structural Context
Position 699 sits in wolframin's C-terminal lumenal domain, immediately preceding W700 (the position of W700S — Cat 2 outlier — and W700C in the Atlas). The AlphaFold model places T699 within 5 Å of TRP700 (2.4 Å), VAL698 (2.5 Å), PHE825 (3.4 Å — W700's aromatic-stacking partner), and SER826 (4.3 Å).
The wild-type threonine at 699 sits in immediate contact with W700 and the F825 aromatic neighbor. The hydroxyl group H-bonds locally and stabilizes the geometry that supports W700's aromatic packing with F825.
Replacing T699 with proline introduces a backbone kink immediately upstream of W700, perturbing the precise W700-F825 π-stacking geometry the Atlas's W700C card identifies as the key functional contact. The |ΔΔG| of 0.14 is small (fold absorbs), but the functional consequence — disrupted W700 stacking — is the same severe pathogenic mechanism that pulls W700C into pathogenic territory.
Druggability Assessment
Mechanism is backbone kink upstream of W700 that perturbs W700-F825 π-stacking geometry. Therapeutic strategy: same target as W700C/W700S — the W700-F825 aromatic stacking microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the T699P PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.